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Scientists Test Potential Targets to Treat Chronic Bowel Disease

COLUMBUS, Ohio – The human digestive system can continue to function even when separated from the rest of the body, a characteristic attributed to the enteric nervous system in the gut wall that regulates movements, secretions, transport and local blood circulation – thus this system is sometimes called the body’s “little brain” because it can act with considerable autonomy.

This feature is helping Ohio State University Medical Center researchers test new therapeutic targets for chronic inflammatory bowel diseases by letting them watch the complex digestive process at work – and how it responds to an experimental drug – in live human tissue samples using laser confocal imaging of the little brain in action.

The scientists have zeroed in on a specific compound, called adenosine, that’s present in all cells of the digestive tract. They found that its release in the normal gut provides fine tuning modulation in the little brain that can be greatly exaggerated by chronic inflammation.

Already having helped prove that adenosine release can activate A1, A2a, A2b or A3 receptors on various cell types to influence the function of the digestive tract in rodent or human gut, the group has now completed animal studies that provide significant new insight to suggest receptors for adenosine make a promising potential target for new drug therapies for inflammatory bowel diseases. Their recent findings were published in a recent issue of the journal Inflammatory Bowel Diseases.

“Our results in animal studies showed that an adenosine A3 receptor agonist drug was effective in protecting the gut against development of inflammation and inflammatory bowel disease at the gene level. Now we are trying to further understand the mechanism of this protective effect,” said Dr. Fievos Christofi, professor and vice chair for research in the department of anesthesiology at Ohio State’s Medical Center and senior author of the study.

The scientists are observing live cell action of diseased tissue samples donated from surgery patients to more comprehensively test their theory that local adenosine A3 receptors and perhaps other receptors are key targets to protecting the digestive system against these diseases, which include Crohn’s disease and ulcerative colitis. The prototype drug they’re testing, IB-MECA, is reported to be entering Phase 2 human clinical trials as a therapy for rheumatoid arthritis, another chronic inflammatory disease.

“Basically we’re following up on an old idea with a new application, trying to see if a drug for rheumatoid arthritis might be useful in treating inflammatory bowel disease,” Christofi said. “I’m very encouraged by the results we’ve had so far in animal studies, and by what others have reported in the literature. And since this drug is already being studied in humans, it has been determined to be safe,” he said, noting that additional studies on its safety and use would be important.

Christofi said the scientists think the adenosine A3 receptor protects the gut on a number of levels, by suppressing free radicals that cause injury to cells and tissues and through anti-inflammatory effects that suppress the excess release of tumor-necrosis factor, other cytokines and other agents that can cause problems in the bowel.

Protection of the “little brain” is another key target being investigated. By reducing the neural activity in the little brain, adenosine or A3 agonists could reduce energy demands in the inflamed gut and help restore energy balance – a form of neural and tissue protection. A drug like IB-MECA may act at several sites to limit or prevent the immune-inflammatory response in experimental inflammatory bowel disease.

The researchers have hope for drugs like IB-MECA or newer, more selective A3 agonists, because other drugs for rheumatoid arthritis – particularly aminosalycilates and methotrexate – already have shown effectiveness in treating inflammatory bowel diseases. Some evidence also suggests that methotrexate may act by elevating endogenous adenosine levels to act at specific receptors, suggesting the possibility that drugs acting through adenosine may have clinical relevance in inflammatory bowel disease.

However, not all chronic inflammation is alike, and triggering events in rheumatoid arthritis differ from those in inflammatory bowel diseases. Further investigation is necessary to confirm the adenosine A3 receptor link, Christofi said, as well as the relative contribution of other receptors, including A2a and A2b, in protection.

“Inflammation is not exactly the same everywhere. It’s a complicated process in the gut initiated by immune activation, possibly triggered by the enteric flora, and is actually an abnormal sustained immune response that gets exaggerated,” he said. “There’s always some low level of inflammation in the gut to prepare it to fight something deleterious to the host. The gut mucosal immune system is the first line of defense against many potentially harmful antigens in food, luminal bacteria or other agents. If that process goes out of control, a patient could potentially develop inflammatory bowel disease.

“Of course it is not quite that simple. The etiology of inflammatory bowel disease is not completely understood, and is the subject of intense investigation by scientists. Genetics, environment and disruption of the mucosal barrier are also contributing factors.”

Once these diseases strike, they typically require lifelong management. Crohn’s commonly affects parts of the small intestine and colon, but can affect any part of the digestive tract. Ulcerative colitis affects the colon. Patients with these diseases usually experience abdominal pain, diarrhea and often weight loss. Many of the estimated 1 million Americans with the diseases undergo surgical treatments to remove damaged tissue in addition to taking medication to control their symptoms and prevent relapse.

“Most patients use a variety of drug therapies, and many of the medications have adverse effects, some more severe. Also, many patients do not stay in remission with drug therapy, eventually requiring surgery, with a likelihood of recurrence. And, in Crohn’s disease in children or adolescents, medications may pose additional difficulties. That’s why scientists are looking for new therapeutic targets. So far, nothing has been identified as the magic bullet for keeping patients in remission,” Christofi said.

In the animal studies, Christofi and colleagues used gene expression profiling to observe the effects of oral IB-MECA on rodents with colitis, and found the drug prevented dysregulation in 92 percent of the genes involved. The dramatic effect of the drug at the gene level is encouraging, Christofi said.

“In human tissues from Crohn’s or colitis surgical cases, antioxidant, anti-inflammatory or neuroprotective effects of A3 or other drugs can be explored. Besides understanding the mechanism by which A3 agonist drugs work, it’s important to test tissues and study how the enteric nervous system is altered and becomes abnormal with IBD, especially those changes involving adenosine or other purine receptors. Then we can see how A3 or other adenosine drugs affect the abnormal behavior of the human gut,” Christofi said. “I think we’re then a small step closer to eventually conducting clinical studies in patients.”

He said the good news is that the Ohio State study found that IB-MECA treatment could prevent adenosine or purine receptor gene dysregulation in experimental colitis – this is protective. Further, a recent analysis by doctoral candidate Leszek Rybaczyk confirmed that adenosine receptors are dysregulated in Crohn’s disease and ulcerative colitis in mucosal biopsies or peripheral blood mononuclear cells.

Notable differences in adenosine receptor expression between experimental and human inflammatory bowel disease underscores the importance of using human tissues to fully understand any new therapeutic target, including the A3 receptor, in the human disease, Christofi said. Understanding abnormalities in adenosine or other purine receptor function may serve to identify additional targets for therapy. There is also a rational basis for exploring the potential use of combinations of adenosine agonists with added benefits in these diseases. Christofi and colleagues also plan to design or use genomic models in which the A3 or other receptors is knocked out or over-expressed to test whether IB-MECA type drugs act only at the A3 receptor for their beneficial effects.

The National Institute of Diabetes and Digestive and Kidney Diseases is providing ongoing funding for some of this research. Ohio State co-authors of the Inflammatory Bowel Disease study are Jorge Guzman, Jun-Ge Yu, Helen Cooke, Jeffrey Palatini, Herbert Auer, Andrey Bozarov, Hamdy Hassan Hassanain, Arturo Cardounel, Asad Javed, Iveta Grants and Jaqueline Wunderlich; other co-authors are Najma Javed from Ball State University, and Zacharias Suntres from Lakehead University, Thunder Bay, Canada.

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